Clinical, laboratory and therapeutic studies are conducted to determine etiology (autoimmunity, neurotoxicity, genetics) of various neuromuscular diseases and design, or apply, effective therapies. Current studies involve patients with: a) inflammatory myopathies with emphasis on inclusion body myositis (IBM); b) inherited vacuolar myopathies with emphasis on hereditary IBM due to GNE mutations and desmin-related myopathies; c) demyelinating polyneuropathies; d) postpolio syndrome; and e) the stiff-person syndrome(SPS). In inflammatory myopathies, the specificity of the T cell Receptors and the in situ clonal expansion of the endomysial T cells are examined longitudinally. The studies have shown that in IBM the T cells are driven by specific antigens. To search for putative antigen(s), T cell clones have been established from the endomysial T cell infiltrates; candidate immunodominant peptides that drive the T cell responses and serve as autoantigens are currently explored using combinatorial peptide libraries. It has been found that in IBM chemokines and costimulatory molecules such as ICOS and ICOS-L are upregulated and the muscle fiber may function as Antigen Presenting cell. Because cytokines share common antigenic determinants with the Alzheimer-like beta-APP amyloid deposits, an ongoing study explores the role of amyloid in triggering endomysial inflammation. The information will be useful in pursuing anti-amyloid strategies as potential therapy for IBM. To suppress the myocytotoxic effect of T cells and their putative role in enhancing the formation of beta-APP, a therapeutic and investigational clinical trial was initiated using CAMPATH, a humanized monoclonal antibody that induces a sustained depletion of mature T cells allowing for toleragenic T cell responses. This study has now started. In demyelinating neuropathies associated with IgM autoantibodies to MAG and glycolipids,a new controlled therapeutic study was initiated using a humanized monoclonal antibody against B cell clones. In an effort to identify peripheral nerve antigens responsible for the neuropathy, the study correlates clinical responses with the binding affinity of IgM to various glycoconjugates on the myelin sheath. Up to 50% of the required patients have alerady participated. In patients with Stiff Person Syndrome (SPS), intrathecal synthesis of anti-GAD-specific IgG antibodies was documented. It was found that GAD antibodies in serum or CSF do not correlate with the clinical symptomatology. In an effort to find responsible autoantigen in SPS patients, T cell clones were established from the CSF and tested against combinatorial peptide libraries. Using proteomics in the patients' serum, a putative antigenic peptide GABARAP (GABA-Receptor Associated Protein) was found to be reduced. Because SPS is an antibody-mediated disorder, a new double-blind clinical trial using a B cell-depleting monoclonal antibody called Rituximab was designed and is ready to begin. The origin of phobias, a common feature in SPS patients, is being explored using a series of neurocognitive measurements. In patients with postpolio syndrome and severe fatigue, a double blind study using Modafinil has been initiated. Clinical improvement is being correlated with the level of fatigue-related cytokines such as TNF-alpha and IL-6. In patients with hereditary IBM due to mutations in the GNE gene we observed defect in glycosylation of muscle proteins and reduction of alpha-dystroglycan. A clinical trial is being designed in an effort to increase muscle glycosylation. A phenotype/genotype correlation has been completed in patients with hereditary myopathies due to pathogenic mutations in the desmin gene. It has been concluded that desmin myopathy is a distinct disease affecting intermediate filaments (filamentopathy) and that the type of mutations may dictate clinical severity or presence of cardiomyopathy.